Major Bleeding. The trigger level for supplementing fibrinogen should be 1.5 to 2.0 g per liter

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4 Major Bleeding Fibrinogen is a critical molecule in coagulation It forms fibrin It is the ligand for platelet aggregation In patients with major bleeding, it is required to a larger extent than any other hemostatic protein This requirement reflects increased consumption, loss, dilution, and fibrinogenolysis The trigger level for supplementing fibrinogen should be 1.5 to 2.0 g per liter It is unknown whether early fibrinogen supplementation and the use of prothrombin complex concentrate, as compared with the use of fresh-frozen plasma, improves clinical outcomes in patients with major bleeding

5 Liver Disease No need to treat prolonged coagulation times in the absence of bleeding If bleeding does occur in liver disease, it is recommend blood component management as determined by the results of testing of the platelet count, prothrombin time, activated partialthromboplastin time, thrombin time, and fibrinogen

6 Renal Disease Uremic bleeding typically presents with ecchymoses, purpura, epistaxis, and bleeding from puncture sites due to impaired platelet function The platelet dysfunction is a result of complex changes that include dysfunctional von Willebrand factor, decreased production of thromboxane, increased levels of cyclic AMP and c yclic GMP, uremic toxins, anemia, and altered platelet granules, all of which are necessary for adequate formation of a platelet plug. The anemia that commonly accompanies renal disease leads to the loss of laminar flow in arterioles so that red cells no longer push platelets and plasma to the endothelium, leading to prolongation of the bleeding time; treatment of the anemia partially corrects this problem. There is also some evidence of impaired fibrinolysis in patients with renal disease.

7 Fibrinolytic Bleeding Bleeding continues despite hemostatic replacement therapy Platelet levels are relatively conserved Fibrinogen levels are disproportionately low D-dimer levels are disproportionately high for disseminated intravascular coagulation Thromboelastography, which may help differentiate fibrinolytic activation from coagulation factor deficiency, is a crude tool, since it detects only the most marked changes The use of tranexamic acid, either by infusion or orally (depending on the severity of the problem and the state of the patient), is beneficial in controlling bleeding.

8 Von Willebrand s Disease Acquired von Willebrand s disease, can be caused by several potential mechanisms due to autoantibodies, myeloproliferative and lymphoproliferative proliferative disorders the breakdown of highmolecular-weight von Willebrand factor multimers owing to high intravascular or extracorporeal circuit shear stresses Acquired von Willebrand s disease is treated with the use of either desmopressin, which stimulates the release of residual stores of von Willebrand factor by endothelial cells, or von Willebrand factor concentrates, with the latter considered to be the more effective therapy The use of antifibrinolytic agents may be considered to alleviate mucocutaneous bleeding

9 Bleeding Associated with Antithrombotic Therapy

10 Sepsis is defined by the presence of Host response Inflammation Infection Disturbances in coagulation Coagulopathy of Acute Sepsis (CAS) Thrombosis Hemorrhage Thromboembolic Disease Microvascular Fibrin Deposition DIC: Disseminated Intravascular Coaugulation Fase precoce Acute traumatic coagulopathy Microvascular Fibrin Deposition Trauma is characterised by the presence of SHOCK-IPOPERFUSIONE COAGULOPATIA Systemic Acquired Coagulopathy (SAC) Fase tardiva Traumatic coagulopathy Endogenous Acute Coagulopathy (EAC) Or Acute Coagulopathy of Trauma Shock (ACoTS)

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13 1. DIC with fibrinolytic phenotype 2. Neurormonal response 3. Anticoagulation and hyperfibrinolysis

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17 Presto! PA < 75!

18 Fulminante < 30min ER: 11 ICU: 2 Sopravvissuti: 0 Schöchl H: J Trauma 2009;67:125 Intermedia min ER: 5 ICU: 6 Sopravvissuti: 1 Tardiva > 60 min ER: 1 ICU: 7 Sopravvissuti: 4

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20 71% pz con Hb<10 63% pz con BE<-6 FIBRINOGENO<150 mg/dl

21 TM Tranex Fibrinogeno PFC Fibrinogeno PPC

22 Early Coagulation Support Protocol In major trauma patients We recommend that each institution implement an evidence-based treatment algorithm for the bleeding trauma patient. (Grade 1B) Trauma patient at risk for massive transfusion Tranexamic acid 1 gr in bolous ev + 1 gr in 8 hous (Grade 1 A) Emergency Room: Venous o arterial blood gas analysis Complete blood count Standard coagulation tests (PT, aptt, Fibrinogen) Blood chemistries Blood typing and cross matching Alto sospetto di emorragia + (almeno 1) SBP < 100 mmhg Hb < 9 g/dl (su EGA) Lac > 6 mosm/l Be < - 6 mmmol/l NO No bleeding risk Blood sample (citrate) for TEG/Rotem SI Tranexamic acid 1 gr in bolous ev + 1 gr in 8 hous (Grade 1 A) se non già somministrato Perform TEG/ROTEM (Grade 1 C) The Team leader starts Early Massive Transfusion protocol: Call hematologist PBRC 4 U (without compatibility test) PBRC 4 U - FFP 4 U - PLT 10 U random Controlls based on standard test (30-40 min) Fibrinogen 2 6 g according MA (Grade1 C); RBC according to Hb level (1 C) If the patient received more than 3 U of PBRC e/o su TEG: FFP or pathogen-inactivated plasma in a plasma-rbc ratio 1:2 (1 B) PLT if PLT < in TBI or if PLT < in the other trauma. Initial dose of 4-8 single platelet units or one aphaeresis pack (Grade 2C) Repeat TEG/ROTEM o PFL (Plasma Fibrinogen Level) for additional fibrinogen Hb between 7 and 9 g/dl Mantain PT and APTT < 1.5 times the normal control (1 C) Avoid plasma in pt without substantial bleeding (1 B)

23 Il paziente è in terapia con anticoagulanti? NO SI REVERSE Tratta come da protocollo Anticoagulanti K-dipendenti 1A Sanguinamento massivo in anticoagulanti non K antagonisti NOAC Fat Xa e Trombina inibitore 2C PPC Alte dosi TXA Anticorpo Mantenendo normali livelli di fibrinogeno (> mg/dl) PPC o Plasma in pz che hanno evidenza di sanguinamento e/o presentano alterazioni alle valutazioni viscoelastiche 2C Raccomandazione

24 Anesth Analg 2014;119: Goal-Directed, POC-Guided Hemostatic Therapy Timing of Intervention Ratio-Driven Volume Resuscitation High Ratio of FFP:RBC

25 PATHOGENESIS OF MULTISYSTEM ORGAN DYSFUNCTION Role DIC High mobility group box 1 - HMGB-1 - (Macrophages, endothelial cells, and monocytes are all capable of releasing HMGB-1 proteins) Neutrophil extracellular traps (NETS) are highly toxic to organs, induce inflammation, and promote thrombosis THROMBOSIS AS A PROTECTIVE MECHANISM IN SEPSIS

26 DISSEMINATED INTRAVASCULAR COAGULATION Highlights Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with this condition. Thrombin generation in DIC proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of PAI-1, contributes to enhanced intravascular fibrin deposition. The diagnosis of DIC can be made by sensitive laboratory tests, however, most of these tests are not readily available in a routine setting. A reliable diagnosis can also be made on the basis of a small series of routine lab tests that can be combined in a scoring algorithm (ISTH-DIC score). The cornerstone of the management of DIC is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation or restoration of anticoagulant pathways have been found beneficial in experimental and initial clinical studies but their effect on clinically relevant outcomes is less clear.

27 And Coagulation?

28 «Early»-goal directed therapy

29 Key Points Inflammation and disturbances in coagulation are inseparably tied, with each acting as positive feedback for activation of the other Coagulation abnormalities are nearly universal in septic patients and likely play a key role in multisystem organ dysfunction Coagulopathy in sepsis is likely driven by derangements of multiple pathways versus a single mediator, which explains why many singe therapies have failed to improve outcomes Therapies directed toward the Coagulopathy of Acute Sepsis should ideally restore the balance of inflammation and coagulation without negatively influencing the host s response to infection Therapeutic strategies are time sensitive and should target patients at high risk for developing DIC So..

30 Viscoelastic and aggregometric point-of-care testing was shown to be potentially useful for bedside diagnosis of sepsis was able to determine the phase of septic coagulopathy (hypercoagulability vs. hypocoagulability) was able to identify patients at high risk for overt disseminated intravascular coagulation Whole Blood Viscoelastic Testing Theoretically, viscoelastic measurements of whole blood should provide clinicians with insight into in-vivo coagulation

31 Patients with sepsis presented with varying viscoelastic results including hypo-, normo- and hypercoagulability, which may be due to varying severity of disease and timing of sampling Only functional fibrinogen MA increased during the observation period, while the median value of the other TEG variables remained relatively constant Hypocoagulable viscoelastic profiles have previously been associated with increased severity of disease more progressive coagulation disturbances such as disseminated intravascular coagulation and increased risk of death Other studies Hypocoagulable 22% Normal 48% Hypercoagulable 30% Patients that were hypocoagulable more often progressed to MODS and death

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34 Hypercoagulable Hypocoagulable

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36 Thromboelastography

37 Acidosi Ipotermia Diluizione Anticoagulanti

38 34% of trauma-related admissions

39 I pz con ROTEM normale 25% ca avevano PLT< ) e aptt >32 s 25% ca presentavano INR >1.5 Il profilo ipocoagulabile presentava più alterazioni del CCT in corrispondenza del profilo di ipocoagulabilità con Trombocitopenia, prolungamento dell aptt ed aumento dell INR. Il 50% dei pz con profilo di ipocoagulabilità presentavano IPOFIBRINOGENEMIA (fibrinogeno <150 mg/dl). Il profilo di ipercoagulabilità frequentemente esibiva un aptt allungato ed un aumento dell INR. 50% ca dei pz profilo CCT e ROTEM normale 25% ca profilo Ipocoagulabilità 25% ca profilo Ipercoagulabilità Il 50% ca dei pz ipercoagulabili presentava una conta piastrinica< Most of the critically ill patients admitted to ICU exhibited a normal coagulation profile according to ROTEM, although CCT suggested presence of coagulopathy. Transfusion therapy based on CCT led to a large number of patients receiving allogeneic blood transfusion, possibly unnecessarily. The use of ROTEM to identify the underlying coagulopathy and as a transfusion guide in this population of critically ill patients has the potential to avoid inappropriate allogeneic blood product transfusions

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44 SYNAPSES Come neuroni siamo tutti interconnessi e parte di una rete culturale sinaptica. Alcuni di noi sono passivi e periferici, altri sono stelle sociali attive, ma tutti svolgiamo un ruolo nella costruzione e trasformiamo l'ambiente sociale in cui viviamo.